My group discovered the direct a-arylation of ketones concurrently with two other groups and has contributed significantly in recent years to the development the a-arylation of many types of carbonyl compounds and nitriles into practical synthetic methods. The relevance of this chemistry to human health has been demonstrated by its use multiple times by process chemists in the past few years to produce clinical candidates on a multi-kilo scale and by its use countless times by medicinal chemists to produce compounds for SAR studies. Further, this chemistry has been used by the academic community to prepare biologically active natural products, and our papers on this topic have been cited hundreds of times. During the past grant period we developed general, coupling reactions of weakly basic zinc and silicon enolates and, sparked by a mechanistic insight, we recently developed highly enantioselective couplings of ketone enolates. These are rare, but important, examples of enantioselective processes that form quaternary stereocenters. We also extended our studies on metal-catalyzed substitutions of enolate nucleophiles during the past grant period to an iridium-catalyzed, enantioselective allylation of silyl enol ethers. The iridium- catalyzed reaction is unusual because it creates a new stereocenter at the allyl electrophile and does so with high enantioselectivity. Our mechanistic studies led us to develop the first reductive eliminations of arylpalladium enolate compounds and to use these compounds to reveal the origins of electronic effects on C-C bond forming reductive eliminations. We also showed that aryl chlorides, bromides and iodides can undergo oxidative addition to the same metal by three different mechanisms. We propose during the next grant period to develop new classes of enolate couplings, including the coupling of aldehydes, aldehyde and ketone surrogates, a,(3-unsaturated carbonyl compounds, and new classes of esters. Based on our recent highly enantioselective couplings of aryl triflates, we propose to develop enantioselective couplings of enolates to form quaternary stereogenic centers and to use weakly basic Zn and Si enolates to conduct enantioselective couplings to form tertiary stereocenters. The rate- limiting step of the catalytic processes is transmetalation of the enolate or oxidative addition of the haloarene to Pd(0). Because little is known about the mechanism of transmetalation and the mechanism of oxidative addition in the presence of halides remains ambiguous, we propose to study the mechanism of a series of transmetalations and to test a new mechanism proposed for oxidative addition in the presence of halides. Finally, we propose to expand the scope of the iridium-catalyzed allylations by conducting reactions with main group enolates and activators we developed for the palladium coupling. We also plan to study the allylation processes using new classes of ligands that are isoelectronic with those in the active catalyst.
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